RPD comprises a variety of genetically determined conditions, which differ from one another in their mode of inheritance, their pattern of visual loss and their clinical ophthalmological appearance. The spectrum of RPDs differ from one another also in their severity, the time of life in which they appear, the type of cells (rods or cones) which are affected, etc.
Another disorder of retinal dystrophy occurs late in life, and involves degenerative changes in the eye's retinal pigment epithelium (RPE), which is a highly pigmented epithelium underlying the retina resulting in photoreceptor and retinal degeneration. Such age-related degeneration occurs mainly in the macular area and will be referred to herein as "AMD" (age-related macular degeneration).
The macula is the area in the eye which enables the discern of small details and reading, and therefore degenerative changes in the macula cause visual impairment and even blindness. AMD in various degrees occurs in about 10% of subjects over 50 and about 30% of subjects over 75.
One of the main factors underlying AMD development is progressive deterioration of the metabolic activity of the RPE. One of the progressive deterioration of the metabolic activity of the RPE. One of the major roles of the RPE is to remove metabolic waste products generated in great abundance during the visual transduction activity of the overlaying retinal photoreceptor cells. AMD, furthermore develops as a result of the RPE's capacity to remove waste products and consequently they accumulate both within the cells and in the extracellular space which leads to a progressive destruction of the RPE cells. Destruction of the RPE cells is followed by progressive degeneration of the overlaying retina, leading eventually to impairment of vision and at times also to total blindness.
Although AMD is the most prevalent cause of blindness in the elderly population in developed countries, there is today no effective treatment available to prevent or delay the development of AMD.
Melanotropins are a group of peptides comprising .alpha.-, .beta.- and .gamma.-melanocyte stimulating hormones (MSH). These are peptide hormones which are produced in the pituitary gland, and are a product of pro-opiomelanocortin, which is also a precursor of the adrenocorticotropic hormone (ACTH) and of .beta.-endorphin. .alpha.-MSH is a N-acetyl tridecapeptide (consisting of 13 amino acids) while .beta.-and .gamma.-MSH have 18 and 12 amino acids, respectively. Melanotropins and especially .alpha.-MSH have been known for their role in regulation of the pigmentary system in vertebrates (Levine et al., 1991). .alpha.-MSH has also been reported as having a number of biological activities including a neurotrophic effect on the growth of neural tissue both in the fetus and in the adult (Eberle, 1988, Ban der Neut, 1988) and stimulating regeneration of peripheral and spinal nerves (Van der Neut et al., 1988; Benelli et al., 1988; Verhagen et al., 1986).
Melanotropins have also been shown to affect skin tanning in humans and clinical trials (Phase I and Phase II) concerned with this indication of melanotropins are now being performed in the U.S.A.
Various effects of .alpha.-MSH on the eye have hitherto been described. .alpha.-MSH was found to accelerate the retinal visual purple regeneration in amphibians in vitro and in vivo and increases the sensitivity of these animals to light (Hanaoka, 1953); to increase release of neuro-transmitters, such as dopamine and GABA, from rabbit's retina in vitro (Bauer et al., 1980); to induce production of eicosanoid in cultured bovine RPE (Bar-Ilan et al., 1992); to increase protein synthesis in RPE of rats with hereditary retinal dystrophy (Stroeva et al., 1988); to have an effect on lacrimal glands, situated outside the eye, which possess receptors for .alpha.-MSH (Leiba et al., 1990).
Derivatives of .alpha.-MSH, in which one or more amino acids has been replaced by another have been described in the art. Some of these derivatives are more stable than the native peptide, and others such as Nle.sup.4 D-PHE.sup.7 .alpha.-MSH (SEQ ID NO: 4) were found to be even more potent than the native peptide in various biological effects (Dayes et al., 1987; Eberle, 1988). It is also known that only a few amino acids of .alpha.-MSH are sufficient to bring about some of the biological activities of the native peptide (Sawyer et al., 1990).